Asymmetric synthesis of axially chiral 1-Aryl-5,6,7,8-tetrahydroquinolines by cobalt-catalyzed [2 + 2 + 2] cycloaddition reaction of 1-Aryl-1,7-octadiynes and nitriles

Article abstract of DOI:10.1021/jo100122d

The asymmetric synthesis of a range of axially chiral 2-arylpyridines by a cobalt-catalyzed [2 + 2 + 2] cycloaddition reaction is described. The use of a planar chiral (1-neomenthylindenyl)cobalt(COD) complex under photochemical conditions is the key for reacting the 1-naphthyldiynes with a range of differently functionalized nitriles, giving the enantiomeric atropoisomers with high chemical yields and enantiomeric excesses of up to 94% ee.

Full text of DOI:10.1021/jo100122d

pubs.acs.org/joc
Asymmetric Synthesis of Axially Chiral
1-Aryl-5,6,7,8-tetrahydroquinolines by Cobalt-Catalyzed [2 þ 2 þ 2]
Cycloaddition Reaction of 1-Aryl-1,7-octadiynes and Nitriles
Marko Hapke,* Karolin Kral, Christine Fischer, Anke Spannenberg, Andrey Gutnov,
Dmitry Redkin, and Barbara Heller
€
Leibniz-Institut fu€r Katalyse e.V. (LIKAT) an der Universitat Rostock, Albert-Einstein-Str. 29a,
D-18059 Rostock, Germany
marko.hapke@catalysis.de
Received January 27, 2010
The asymmetric synthesis of a range of axially chiral 2-arylpyridines by a cobalt-catalyzed [2 þ 2 þ 2]
cycloaddition reaction is described. The use of a planar chiral (1-neomenthylindenyl)cobalt(COD)
complex under photochemical conditions is the key for reacting the 1-naphthyldiynes with a range of
differently functionalized nitriles, giving the enantiomeric atropoisomers with high chemical yields
and enantiomeric excesses of up to 94% ee.
Introduction
have been found to be one of the most popular and versatile
methodologies for this purpose.4 Among the different cross-
coupling reactions the asymmetric Suzuki-Miyaura cou-
pling has since the developments during the past decade
proven to be most versatile and valuable for the preparation
of specific chiral biaryls.5 Another important method that
has initially seen largely achiral applications in biaryl synthesis
partially coupled with subsequent resolution of the racemates
is the transition-metal-mediated oxidative coupling of arenes.6
Recently, an increasing number of asymmetric metal-catalyzed
oxidative couplings have been studied, especially those based
The synthesis of axially chiral biaryls has attracted a lot of
attention in the recent decades due to the emergence in a large
number of natural products containing structures with a
stereogenic biaryl axis, chiral auxiliaries and as ligands of
catalyst systems.1 Furthermore, their chiral element atrop-
isomerism has received increased attention because of its
occurrence in different drugs.2 Although a number of chiral
biaryls are commercially available, a set of methodologies
for the direct stereoselective access to compounds possessing
a chiral biaryl fragment and avoiding separation steps has
been explored.3 The experimental work reported so far
showed that asymmetric catalytic cross-coupling reactions
~
(4) General overviews: (a) Bolm, C.; Hildebrand, J. P.; Muniz, K.;
Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284. (b) Wallace, T. W.
Org. Biomol. Chem. 2006, 4, 3197.
(1) (a) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Cata-
lysis; University Science Books: Sausalito, CA, 2009. (b) For an extensive review,
see: Bringmann, G.; Price Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384.
(5) Recent work: (a) Uozumi, Y.; Matsuura, Y.; Arakawa, T.; Yamada,
Y. M. A. Angew. Chem., Int. Ed. 2009, 48, 2708. (b) Bermejo, A.; Ros, A.;
ꢀ
Fernandez, R.; Lassaletta, J. M. J. Am. Chem. Soc. 2008, 130, 15798.
(c) Sawai, K.; Tatumi, R.; Nakahodo, T.; Fujihara, H. Angew. Chem., Int.
Ed. 2008, 47, 6917. (d) Genov, M.; Almorın, A.; Espinet, P. Tetrahedron:
Asymmetry 2007, 18, 625. (e) Genov, M.; Almorın, A.; Espinet, P. Chem.;
Eur. J. 2006, 12, 9346. Overview on the early developments: (f) Baudoin, O.
Eur. J. Org. Chem. 2005, 4223.
(2) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew.
Chem., Int. Ed. 2009, 48, 6398.
(3) General reviews on transition-metal-mediated aryl-aryl coupling
ꢀ
reactions: (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359. (b) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174.
(6) Lessene, G.; Feldman, K. S. In Modern Arene Chemistry; Astruc, D.,
Ed.; Wiley-VCH Verlag: Weinheim, 2002; p 479.
DOI: 10.1021/jo100122d
r
Published on Web 05/19/2010
J. Org. Chem. 2010, 75, 3993–4003 3993
2010 American Chemical Society

Hapke et al.
JOCArticle
on copper, vanadium, and ruthenium complexes containing
chiral ligands.7
SCHEME 1. Chiral Cobalt(I) Catalyst 1
In the recent decade the [2 þ 2 þ 2] cycloaddition reactions
haveevolved intoa versatilememberof the synthetic chemists’
toolbox for the preparation of functionalized arenes.8 Its
potential as a key transformation in total synthesis has been
demonstrated.9 Cobalt complexes have continuously found
widespread use in a number of cycloaddition reactions, and
new catalyst complexes have been reported.10 However, the
use of CpCo(COD) in combination with irradiation for the
activation of the catalyst turned out to be an especially mild
method.8e,11 It can be used in combination with asymmetric
reactions, such as, e.g., cyanations for the racemization-free
preparation of chiral compounds.12 We first reported chiral
cobalt(I) catalysts suitable for the asymmetric version of
the [2 þ 2 þ 2] cycloaddition reaction,13 in particular for the
preparation of atropoisomeric chiral pyridines and biaryls.14
The catalyst complex 1a/b has been found to be most effective
for this kind of transformation (Scheme 1), which otherwise
needed an additional resolution step.15 Others have developed
TABLE 1. Asymmetric Synthesis of Enantiomeric Isoquinolines Using
the Chiral Co Complex 1b
nitrile
biaryl
T (°C)
yielda (%)
selectivity (% ee)b
PhCN (3)
MeCN (4)
t-BuCN (5)
6
7
8
-20
3
3
86
88
74
93
88
88
(7) Chiral Cu complexes: (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C.
Chem. Soc. Rev. 2009, 38, 3193 and references cited therein. Chiral V complexes:
(b) Takizawa, S.; Katayama, T.; Sasi, H. Chem. Commun. 2008, 4113 and
references cited therein. Chiral Ru complexes: (c) Irie, R.; Masutani, K.; Katsuki,
T. Synlett 2000, 1433.
aYield after chromatography. bMeasured in reaction mixture.
catalyst systems based on Rh or Ir complexes.16,17 The use of
these late transition metals in the selective preparation of
atropochiral biaryls has been compiled only recently.18
We report here on our investigations using the chiral
cobalt(I) complex 1 for the preparation of functionalized
chiral biaryls using different diynes and nitriles to gain
information on the broadness of this particular cobalt-based
asymmetric methodology and structural features required to
obtain good yields and high enantioselectivities.
(8) Recent reviews: (a) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009,
ꢀ
48, 2830 and references cited therein. (b) Varela, J. A.; Saa, C. Synlett 2008, 2571.
ꢀ
(c) Scheuermann nee Taylor, C. J.; Ward, B. D. New J. Chem. 2008, 32, 1850.
(d) Hess, W.; Treutwein, J.; Hilt, G. Synthesis 2008, 3537. (e) Agenet, N.; Busine,
O.; Slowinski, F.; Gandon, V.; Aubert, C.; Malacria, M. Org. React. 2007, 68, 1.
(f) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085. (g) Tanaka, K. Synlett
2007, 1977. (h) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307.
(9) First reported use in the synthesis of (()-estrone: (a) Funk, R. L.;
Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102, 5253 and references cited
therein. Recently reported example: (b) Nicolaou, K. C.; Tang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2009, 48, 597. (c) Li, P.; Menche, D. Angew. Chem.,
Int. Ed. 2009, 48, 5078.
(10) Examples: (a) Geny, A.; Agenet, N.; Iannazzo, L.; Malacria, M.;
Aubert, C.; Gandon, V. Angew. Chem., Int. Ed. 2009, 48, 1810. (b) Hilt, G.;
Hengst, C.; Hess, W. Eur. J. Org. Chem. 2008, 2293.
Results and Discussion
(11) (a) Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H.-J.; You,
J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67, 4414.
(b) Heller, B.; Sundermann, B.; Fischer, C.; You, J.; Chen, W.; Drexler, H.-J.;
Knochel, P.; Bonrath, W.; Gutnov, A. J. Org. Chem. 2003, 68, 9221.
(c) Gutnov, A.; Abaev, V.; Redkin, D.; Fischer, C.; Bonrath, W.; Heller,
B. Synlett 2005, 1188.
(12) Heller, B.; Redkin, D.; Gutnov, A.; Fischer, C.; Bonrath, W.; Karge,
R.; Hapke, M. Synthesis 2008, 69.
(13) Synthesis of the chiral cobalt(I) complexes: (a) Gutnov, A.; Drexler,
H.-J.; Oehme, G.; Spannenberg, A.; Heller, B. Organometallics 2004, 23,
1002. (b) Gutnov, A.; Heller, B.; Drexler, H.-J.; Spannenberg, A.; Oehme, G.
Organometallics 2003, 22, 1550.
During our initial experiments, we investigated the use of
catalyst 1a or 1b for the preparation of chiral isoquinoline
derivatives from diynes and rather simple nitriles containing
alkyl groups or a phenyl group as the only substituents.14 The
obtained results showed that the performance of the reaction of
diyne 2 with benzonitrile (3), acetonitrile (4), or tert-butylnitrile
(5) and catalyst 1b under irradiation of the reaction mixture
with visible light (λ = 350-500 nm) led to successful asym-
metric induction in the cycloaddition process, yielding the
desired (R)-configured atropochiral isoquinolines 6-8 with
very good yields and enantioselectivities (Table 1).
(14) (a) Gutnov, A.; Heller, B.; Fischer, C.; Drexler, H.-J.; Spannenberg,
A.; Sundermann, C.; Sundermann, B. Angew. Chem., Int. Ed. 2004, 43, 3795.
(b) Heller, B.; Gutnov, A.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.;
Redkin, D.; Sundermann, C.; Sundermann, B. Chem.;Eur. J. 2007, 13, 1117.
The screening for the optimal reaction conditions proved
-20 °C as the optimal temperature for obtaining the highest
enantiomeric excess for the cycloaddition product while at
higher temperatures slightly lower selectivities were observed.
Our hitherto obtained data show that the chirality of the
intact catalyst provided by the neomenthyl group attached
to the indenyl ring is responsible for the chiral induction
during the cycloaddition process. This also rules out any other
predominant catalyticallyactivespeciesthat might result from
the decomposition of the chiral complex 1 leading to metallic
cobalt, which has also been shown to be catalytically active.19
ꢀ
ꢀ
ꢁ ꢀ
(15) Hrdina, R.; Stara, I. G.; Dufkova, L.; Mitchel, S.; Cısarova, I.;
Kotora, M. Tetrahedron 2006, 62, 968.
(16) Recent examples for Rh-catalyzed reactions: (a) Oppenheimer, J.;
Johnson, W. L.; Figueroa, R.; Hayashi, R.; Hsung, R. P. Tetrahedron 2009,
65, 5001. (b) Imase, H.; Suda, T.; Shibata, Y.; Noguchi, K.; Hirano, M.;
Tanaka, K. Org. Lett. 2009, 11, 1805. (c) Doherty, S.; Smyth, C. H.;
Harrington, R. W.; Clegg, W. Organometallics 2008, 27, 4837. (d) Nishida,
G.; Ogaki, S.; Yusa, Y.; Yokozawa, T.; Noguchi, K.; Tanaka, K. Org. Lett.
2008, 10, 2849. (e) Shibata, T.; Otomo, M.; Tahara, Y.; Endo, K. Org.
Biomol. Chem. 2008, 6, 4296. (f) Review: Tanaka, K. Synlett 2007, 1977.
(g) Nishida, G.; Noguchi, K.; Hirano, M.; Tanaka, K. Angew. Chem., Int. Ed.
2007, 46, 3951.
(17) Recent examples for Ir-catalyzed reactions: (a) Review: Shibata, T. In
Iridium Complexes in Organic Synthesis; Oro, L. A., Claver, C., Eds.; Wiley-
VCH Verlag: Weinheim, 2009; p 277 and references cited therein.
(18) Tanaka and Shibata have very recently compiled the use of transition-
metal-catalyzedasymmetric [2þ 2 þ 2] cycloaddition reactions in the synthesis
of chiral biaryls; see: (a) Tanaka, K. Chem. Asian J. 2009, 4, 508. (b) Shibata,
T.; Tsuchikama, K. Org. Biomol. Chem. 2008, 6, 1317.
(19) See: (a) Vitulli, G.; Bertozzi, S.; Lazzaroni, R.; Salvadori, P.
J. Organomet. Chem. 1986, 307, C35. (b) Vitulli, G.; Bertozzi, S.; Vignali,
M.; Lazzaroni, R.; Salvadori, P. J. Organomet. Chem. 1987, 326, C33.
3994 J. Org. Chem. Vol. 75, No. 12, 2010

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TABLE 2. Screening of Different Nitriles
FIGURE 1. Proposed cobaltacyclopentadienyl intermediate (9) of
the cycloaddition reaction.
The initial idea for the formation of the chiral axis of the biaryl
products points out that the chirality will be preformed in the
cobaltacyclopentadienyl intermediate, which isformedduring
the oxidative cyclization process between the metal center and
the two alkyne moieties. The subsequent coordination of the
substrate nitrile molecule then only fixes the conformation,
which has already been formed, no matter if it coordinates
side-on or end-on to the cobalt center.20 The energy-minimized
structure (B3LYP/6-31G*) of the potential intermediate (9)
derived from 1a with end-on coordinated nitrile is displayed in
Figure 1.
For the evaluation of further structural parameters in the
diyne and nitrile substrates, which can play a significant role
in the outcome (yield, selectivity) of the reaction, we first
investigated the reaction of diyne 2 with an array of different
nitriles (Table 2). In general, we used the optimized reaction
conditions at -20 °C for the evaluation of the nitrile
substrates to obtain comparable results.
The reaction usually requires 1-2 mol % of catalyst 1b
and 48-72 h irradiation time at -20 °C to be completed. The
yields are in general moderate to very good, and the selecti-
vities are generally above 75% ee. An exception is the use of
nitrile 11, possessing an ortho substituent, where 5 mol % of
1b was needed for the reaction to yield reasonable amounts
of biaryl 21. The reaction became extremely sluggish when
using the more hindered 2,4,6-trimethoxybenzonitrile even
at 20 °C, and only traces of the corresponding product were
determined at all. The examination of benzonitriles substi-
tuted at the 4-position, like 12-15 (entries 5-8, Table 2), gave
lower yields compared to alkyl-substituted nitriles (entries 1,
2, and 12, Table 2) regardless of the electronic nature of the
substituent. Furthermore, the nature of the substituent in the
4-position seems to have little effect on the selectivity, as
exemplified by comparing entries 5 and 6 in Table 2. However,
the yield of biaryl 23 for the reaction of 2 with 4-dimethyla-
minobenzonitrile (13) gave only around 6% yield of 23 with
81% ee selectivity at a reaction temperature of -20 °C.
aYieldafter chromatography. bMeasuredin reaction mixture.c1 mol %
e
f
of catalyst 1b. d2 mol % of catalyst 1b. 5 mol % of catalyst 1b. Not
determined. gNo further characterization.
Performing the reason at -10 °C provided 23 in much
higher yield with no loss in selectivity. The use of
4-chlorobenzonitrile (14) gave only a 10% yield at a reaction
temperature of 5 °C, and no further optimization was tried.
The interesting boryl group-functionalized biaryl 25 resulted
(20) The modes of coordination of the nitrile to the cobalt center have
been discussed on the basis of computational data: (a) Dahy, A. A.; Yamada,
K.; Koga, N. Organometallics 2009, 28, 3636. The reaction pathways of the
cyclotrimerization of alkynes was also the subject of detailed theoretical
studies: (b) Agenet, N.; Gandon, V.; Vollhardt, K. P. C.; Malacria, M.;
Aubert, C. J. Am. Chem. Soc. 2007, 129, 8860.
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TABLE 3. [2 þ 2þ2] Cycloaddition Reactions Using Naphthyldiynes
However, the yields were very low in the cases at low
temperature (9-20%, entries 1, 2, 4, and 6) and acceptable
at +3 °C. Compound 34 could only be isolated containing
small amounts of impurities. The presence of a free hydroxyl
group as in diyne 33 obviously has no significant influence on
the outcome of the cycloaddition process in either direction.
We exemplarily investigated the cocyclotrimerization reac-
tion at a higher reaction temperature (þ3 °C) for diynes 31
and 32. The results showed, in analogy to earlier observa-
tions, that at higher temperatures the yields were strongly
improved, and accordingly slightly lower selectivities are
usually observed, as exemplified for biaryl 36 (entry 5). Inter-
estingly, for biaryl 35 with 55% ee, a higher selectivity was
observed than at lower temperature (entry 3), which ap-
pears unusual. However, this might be due to problems of
determination of the selectivity due to the low yield at the
reaction temperature of -20 °C (entry 2). In comparison,
the substituent in the 2-position of the naphthyl ring seems
to have a higher impact, especially on the selectivity of the
cycloaddition process compared to the nature of the nitrile
used (Table 2). The rather small methoxy substituent there-
fore proves to be a highly suited functionality, as was
disclosed for the carboxy methyl ester group in 36.
30-33 Differently Functionalized in the 2-Position
entry diyne biaryl T/t (°C/h) yielda (%) selectivity (% ee)c
1
2
3
4
5
6
30
31
31
32
32
33
34
35
35b
36
36
37
-20/72
-20/72
þ3/36
11
9
50
17
65
20
52d
22d
55
90
87
-20/72
þ3/48
-20/72
36
aYield after chromatography. b5 mol % of catalyst 1b was used.
cMeasured in the isolated products. dDetermination of selectivity was
difficult due to small amounts of product: the given value represents the
most reliable result from the measurements.
from thesuccessful reaction of 2 withnitrile15withacceptable
yield and slightly lower selectivity compared to other nitriles.
For the reaction of the heterocyclic nitriles 17 and 18 with
diyne 2, the reactions yielded the product either with very low
(ca. 13% for 27) or basically no yield even at 20 °C for 28.
In both cases, when either 17 or 18 was used, the reaction
mixture turned red to violet over the course of the reaction,
showing the typical color of cobalt complexes with hetero-
cyclic ligands (vide infra). This is in contrast to the use of furan
derivative 16, which gave the expected cyclization product 26
with excellent enantioselectivity and very good yield. Finally,
whenN-cyanopiperidine(19, entry 12, Table2)was used, both
high yield and selectivity were obtained, thus making these
results comparable to the values obtained for alkyl-substi-
tuted nitriles 4 and 5 (entries 1 and 2, Table 2), containing no
heteroatom. Obviously, the nitrogen adjacent to the nitrile
functionality lacks a negative influence on the cycloaddition
reaction, contributing to the generality of the methodology.
We also investigated the effects of structural variation of
the substituent in the 2-position of the diyne naphthyl ring
system. Several diynes 30-33 bearing different functional-
ities, such as esters, ether, or a free hydroxyl group, were
synthesized for this purpose in general using the standard
Sonogashira coupling methodology.21 Diyne 33 possessing a
free hydroxyl group was conveniently prepared from diyne
32 by reduction of the ester functionality with Red-Al,
yielding 33 directly with acceptable yield (69%). The cocy-
clotrimerization experiments of 30-33 with benzonitrile (3)
were performed according to the conditions given in Table 3.
Surprisingly, in the reactions performed at -20 °C, a high
selectivity of 90% ee was observed only for the methyl ester
substituted biaryl 36 (entry 4). In all other cases, the selecti-
vities were rather low, especially when the results were
compared with the selectivities reported in Table 2. The best
selectivity after 36 was obtained in the case of biaryl 34 with
the pivaloyl-protected hydroxyl group in the 2-position,
although only 52% selectivity was determined (entry 1).
The observed incompatibility of the cycloaddition reac-
tion with heterocyclic nitriles containing sulfur or nitrogen
was exemplarily addressed for 2-cyanopyridine (18). The
expected reaction product 28 would contain the 2,20-bipyr-
idine moiety, which is one of the most widely used bidentate
ligands for transition-metal complexes.22 It is proposed that
the formation of biaryl 28 would give rise to the formation
of a stable cobalt(I) complex, leading to an inhibition of cata-
lytic activity after formation of small amounts of 28. To
prevent this problem, the protection of the nitrogen atom in
28 was considered, which would yield a product without
possessing the strong coordination abilities of the 2,20-bipyr-
idine fragment. A simple protection can be made by the
formation of the N-oxide of 28, which is an easy accessible
yellow solid.23 However, use of the N-oxide was found to be
unsuccessful because no biaryl product from the cobalt-
catalyzed cycloaddition process was observed. The fast
darkening of the reaction mixture unlike the other reactions
presumably indicated the occurrence of some unwanted side
reactions or catalyst decomposition under our reaction con-
ditions. Therefore, we decided to investigate the inhibition
process, which is assumed in the reaction of diyne 2 with
nitrile 18. For this purpose, we synthesized the CpCo(I)-
2,20-bipyridine complex, CpCo(bpy), independently as a
model compound for the catalyst inhibition product and
proved its structure by X-ray crystallography (Scheme 2).24
We also investigated if this exchange reaction can occur
under photochemical conditions and found that in the reac-
tion of CpCo(COD) with 1 equiv of bpy in THF-d8 the
expected complex CpCo(bpy) is indeed formed in a 3:1 ratio
with unreacted starting material after 36 h of irradiation. The
€
(22) (a) Hapke, M.; Brandt, L.; Lutzen, A. Chem. Soc. Rev. 2008, 37,
2782. (b) Newkome, G. R.; Patri, A. K.; Holder, E.; Schubert, U. S. Eur. J.
Org. Chem. 2004, 235. (c) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev.
2000, 100, 3553.
(23) Ochiai, E. J. Org. Chem. 1953, 18, 534.
(24) The complex was prepared according to the following work:
(a) Jonas, K.; Deffense, E.; Habermann, D. Angew. Chem., Int. Ed. Engl.
1983, 22, 716. (b) Hapke, M.; Spannenberg, A. Acta Crystallogr. 2009, E65,
m93–37.
(21) The detailed synthetic procedures are given in the Experimental
Section.
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SCHEME 2. Synthesis of a CpCo(I)-Bipyridine Complex
SCHEME 4. Synthesis of Diynes 39-43
SCHEME 3. Investigation of the Inhibition of Cycloaddition
Reactions by 2,20-Bipyridine as the Chelating Ligand
stable and observable cobalt complex which is able to inhibit
the cycloaddition reaction under our reaction conditions.
Structural parameters of the products can be a key to success,
ꢀ
as demonstrated by Saa et al., who showed that 3-substituted
2,20-bipyridines can be made successfully by cycloaddition
reactions using CpCo(CO)2 as the catalyst. This can be
explained because substituents in the 3-position prevent the
optimal planar arrangement of both pyridine rings necessary
for the most effective complexation of the metal center.25
However, work by Chelucci et al. provided the possibility of
synthesizing substituted 2,20-bipyridines successfully using
CpCo(COD) as the catalyst with acetylene under rather
harsh conditions.26 Contrary to the behavior of the reagent
based on the CpCo fragment are reagents prepared from
cobalt(II) salts, bisphosphanes, and reductants like elemen-
tary zinc, as reported by Okamoto et al.27 The generated
catalysts yield a large array of 2,20-bipyridines, including a
few examples of 3-unsubstituted 2,20-bipyridines with mostly
high yields. Obviously, these catalysts are less susceptible to
catalyst inhibition under the reaction conditions reported
(50 °C, NMP as the solvent) compared to our approach.
To further investigate structural details and requirements
for the cycloaddition reaction we evaluated the reactivity of
several diyne substrates, containing different spacer units
between the two alkyne functionalities. For this purpose, we
needed to synthesize the various diynes 39-43 from 1-iodo-
2-methoxynaphthalene (38) and the appropriate diyne using
sp2-sp cross-coupling methodologies (Scheme 4).28 We utilized
two slightly different coupling conditions. Procedure A used a
protocol developed by Crisp et al. based on the use of ZnCl2
and piperidine together with Pd(PPh3)4 as the catalyst.29 For
procedure B, traditional palladium-catalyzed Sonogashira
reaction conditions were applied while adding the naphthyl
iodide 38 continously over time via a syringe pump. The
isolated yields for both methods are in the same range between
55 and 66%, except for the coupling of 38 with dipropargyl
bipyridine complex formation was proved by comparison
with the 1H NMR spectra of a solution of isolated CpCo(bpy)
in THF-d8. Four protons of the coordinated 2,20-bipyridine
present remarkable proton NMR shifts (10.2 and 6.7 ppm),
which are diagnostic for the coordination. The exchange
process can furthermore be observed optically by the rapid
change of color leading to an intense purple upon irradiation
of the clear yellow solution.
Evaluation of complex CpCo(bpy) as catalyst in the
cycloaddition reaction between diyne 2 and PhCN (3)
showed that no consumption of either the diyne or the nitrile
was observed (Scheme 3). However, when CpCo(COD) and
2,20-bipyridine were added separately to the reaction mix-
ture, the inhibition depended on the amount of bpy added. In
the case of a slight excess of bpy with respect to CpCo(COD)
the conversion of the diyne is still 49%, while with 6 equiv of
bpy the conversion is only about 6%. These results can be
therefore interpreted to mean that with only a slight excess of
bpy added the cycloaddition reaction is not immediately
completely inhibited and 6 can be formed to a certain extent.
On the other hand, a large excess of bpy quickly led to the
photochemical exchange reaction presented above, forming
CpCo(bpy) as a catalytically completely inactive cobalt species.
As a final NMR experiment, we reacted CpCo(COD) with
a slight excess of diyne 2 and 2-cyanopyridine (18) in THF-d8
in a sealed tube. The 1H NMR analysis after irradiation for
14 h at 10 °C showed the large consumption of diyne 2 and
about one-third of the CpCo(COD), indicated by the for-
mation of free COD. The characteristically shifted signals for
the formation of a CpCo-bipyridine complex were again
observed in the proton NMR. The formation also became
optically recognizable because we again observed the forma-
tion of a strongly colored reaction solution after a short
irradiation time. After workup, the formation of biaryl 28
was corroborated by ESI mass spectroscopy. These findings
can therefore be interpreted to mean that the presence of 2,20-
bipyridine as a structural fragment of the reaction product 28
from the cocyclotrimerization of 18 with 2 can indeed form a
ꢀ
(25) (a) Varela, J. A.; Castedo, L.; Saa, C. J. Am. Chem. Soc. 1998, 120,
12147. (b) Varela, J. A.; Castedo, L.; Maestro, M.; Mahıa, J.; Saa, C.
ꢀ
Chem.;Eur. J. 2001, 7, 5203.
(26) (a) Chelucci, G. Tetrahedron: Asymmetry 1995, 6, 811. (b) Botteghi,
C.; Chelucci, G.; Chessa, G.; Delogu, G.; Gladiali, S.; Soccolini, F.
J. Organomet. Chem. 1986, 304, 217. The cycloaddition reaction was
performed at 100 °C with a high acetylene pressure (12 atm).
(27) Goswami, A.; Ohtaki, K.; Kase, K.; Ito, T.; Okamoto, S. Adv. Synth.
Catal. 2008, 350, 143.
(28) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(29) Crisp, G. T.; Turner, P. D.; Stephens, K. A. J. Organomet. Chem.
1998, 570, 219.
J. Org. Chem. Vol. 75, No. 12, 2010 3997

Hapke et al.
JOCArticle
TABLE 4. Synthesis of Pyridine Derivatives with Various Ring Systems
in the Backbone
entry diyne biaryl T/t (°C/h) yielda (%) selectivity (% ee)
1
2
3
4
5
39
40
41
42
43
44
45
46
47
48
-20
-20
þ5
72
64
59b
c,d
þ3
d
þ3
aYield after chromatography. bUsing 5 mol % of CpCo(COD) as
catalyst. c6% conversion by GC. dReactions using 3 and the terminally
unsubstituted diynes under the same conditions for comparison did not
yield any cycloaddition product either.
FIGURE 2. Dynamic HPLC of pyridine 44.
free rotation was already observed at 20 °C. The analogous
analytical chiral HPLC separation of 46 surprisingly turned
out to be unsuccessful, and the enantiomers appeared to be
inseparable, even when going to very low temperatures (up to
-20 °C).31 The observations are in contrast to those for the
enantioselective synthesis of five-membered ring-annulated
1,4-diarylbenzenes via iridium-catalyzed [2 þ 2 þ 2] cycload-
dition reactions from diynes and monoalkynes as recently
reported by Shibata et al.32 The products they obtained
showed no racemization under conditions requiring up to
100 °C reaction temperature, therefore exhibiting a greatly
enhanced stability of the configuration of the biaryl axis. It
can be assumed that the presence of the sterically less
demanding nitrogen (in comparison to the benzene C-H
group) in the formed pyridine rings might play a vital role for
the missing configurational stability of 44-46.
ether giving diyne 41, where only 35% of the pure product was
isolated.
The investigation of the [2 þ 2 þ 2] cycloaddition reaction
of diynes 39-43 with benzonitrile (3) that could lead to
either five-membered or larger rings in the backbone of the
newly formed annelated pyridine was performed using
catalyst 1b or CpCo(COD) (Table 4). The results clearly
show that the biaryls 44-46 (entries 1-3) can be formed in
good chemical yields, but no enantiomeric excess was
observed under these reaction conditions in either case.
The use of diynes containing larger alkyl spacers between
the alkyne moieties like in 42 and 43 should give rise to the
formation of 7- or 8-membered rings in the backbone of the
biaryls 47 and 48, which are presumably rather stable
against racemization around the biaryl axis. However, in
these cases very low conversions or even no biaryl forma-
tion at all was observed. Control experiments using the
terminally unsubstituted corresponding diynes did not
yield any cycloaddition product either.
Conclusion
In summary, we presented an investigation of the asym-
metric cobalt-catalyzed cocyclotrimerization between a
range of diynes and a number of differently functionalized
nitriles. The reaction can be successfully performed in gene-
ral at -20 °C under optimized irradiation conditions, yielding
the enantiomeric tetrahydroquinolines with mostly good
yields and ee’s up to 94%. We also took a closer look at the
catalyst inactivation by product inhibition for heterocyclic
nitriles that can form unhindered chelating ligands in the
cyclization process. Finally, the synthesis of biaryls possessing
a five-membered ring annulated at the pyridine moiety was
investigated, and we found that the size of the ring is too small
to prevent the slippage of the rings around the biaryl axis due
to the presence of the ring nitrogen. Therefore, no enantios-
electivity can be observed, although the obtained isolated
yields were good. We are working toward the application of
the cobalt-catalyzed process and the reaction of new sub-
strates presenting interesting structural parameters.
For a more detailed investigation on the lack of selectivity
in the preparation of biaryls 44-46 we decided to use
dynamic chiral HPLC because we were keen to find out to
what extent the obvious instability of the formed biaryl axis
is responsible for the racemization of the products. The
investigation showed (Figure 2 shows the spectra for 44)
that at low temperatures (0 °C) both enantiomeric forms
exist and that they can be separated under isothermic HPLC
conditions. However, raising the temperature led to an
increase of the plateau between the separated signals which
belong to the achiral form, showing free, unhindered rota-
tion around the biaryl C-C axis at temperatures higher than
30 °C. The free energy barrier to interconversion of the
enantiomers of compound 44 was calculated to be ΔGq =
89 kJ mol-1 at 20 °C.30 The barrier for the methylamino-
substituted analogue 45 was found to be slightly lower, and
(30) The quantitative treatment of the HPLC spectra and the calculation
of the energy barrier for the interconversion from the rates following the
Arrhenius equation was performed after: (a) Thede, R.; Haberland, D.;
Fischer, C.; Below, E.; Langer, S. H. J. Liq. Chromatogr. Relat. Technol.
1998, 21, 2089. (b) For more recent approaches, see: Trapp, O. Chirality 2006,
18, 489 and cited references.
(31) The dynamic HPLC spectra for 45 and 46 can be found in the
Supporting Information.
(32) Shibata, T.; Arai, Y.; Takami, K.; Tsuchikama, K.; Fujimoto, T.;
Takebayashi, S.; Takagi, K. Adv. Synth. Catal. 2006, 348, 2475.
3998 J. Org. Chem. Vol. 75, No. 12, 2010

Hapke et al.
JOCArticle
Experimental Section
J = 8.0, 6.9, 1.2 Hz), 7.21 (d, 1H, J = 8.8 Hz), 1.56 (s, 9H) ppm.
13C NMR (75 MHz, CDCl3): δ = 176.2, 150.2, 135.2, 131.9(2),
130.0, 128.3, 128.1, 126.2, 121.3, 94.3, 39.3, 27.4 ppm. MS (70 eV)
m/z: 354 (15) [Mþ], 270 (100), 114 (13), 57 (16). Diyne 30 was
prepared following general procedure 2 from 1-iodonaphthalen-
2-yl pivalate (1.3 g, 3.67 mmol) and 1,7-octadiyne (1.16 g, 11.0
mmol) as well as Pd(PPh3)4 (0.25 g, 0.22 mmol) as the catalyst,
giving 450 mg (37%) of pure diyne 30 after chromatography on
silica gel with petroleum ether/ethyl acetate (6:1 v/v). 1H NMR
(300 MHz, CDCl3): δ = 8.31 (d, 1H, J = 8.3 Hz), 7.83 (d, 1H,
J = 8.0 Hz), 7.79 (d, 1H, J = 8.9 Hz), 7.57 (ddd, 1H, J = 8.3, 6.9,
1.4 Hz), 7.49 (ddd, 1H, J = 8.0, 6.9, 1.3 Hz), 7.19 (d, 1H, J =
8.9 Hz), 2.61 (t, 2H, J = 6.8 Hz), 2.29 (td, 2H, J = 6.7, 2.6 Hz),
General Procedures for the Synthesis of the Monoarylated
Diynes. General Procedure 1. 1-Naphthyl halides (30 mmol),
Pd(PPh3)4 (1.74 g, 1.5 mmol), ZnCl2 (818 mg, 6 mmol), piper-
idine (75 mL), diynes (60 mmol), and I2 (20 mg) were stirred for
6 h at 70 °C under argon atmosphere. The reaction mixture was
cooled to rt, diluted with an n-hexane-Et2O mixture (5:3),
and stirred for an additional 1 h. Precipitated solids were filtered
off and washed with the same mixture of solvents. The mother
liquor was evaporated at high vacuum, and the products were
separated by chromatography on silica gel using n-hexane-
Et2O or petroleum ether/ethyl acetate in different proportions
as the eluent.
2.00 (t, 1H, J = 2.6 Hz), 1.87-1.74 (m, 4H), 1.46 (s, 9H) ppm. 13
C
General Procedure 2. The catalyst system (6 mol %, either
Pd(PPh3)4 or Pd2dba3 CHCl3/2 dppf) and CuI (15 mol %) were
NMR (75 MHz, CDCl3): δ = 176.7, 150.4, 134.3, 131.3, 128.9,
128.2, 127.1, 126.2, 126.0, 121.3, 113.7, 99.9, 84.1, 74.1, 68.8,
39.3, 27.8, 27.7, 27.4, 19.6, 18.1 ppm. MS (70 eV) m/z: 331 (15)
[M - H]þ, 275 (100), 247 (93), 233 (29), 219 (50), 205 (16), 191
(15), 181 (30), 165 (26), 152 (41), 57 (77). HRMS (ESI) for
C23H25O2: calcd 333.1849, found 333.1849.
3
suspended in ca. 15 mL of THF in a Schlenk flask and stirred
for several minutes, and then ca. 100 mL of NEt3 as well as the
diyne (2 equiv) were added. A solution of the naphthyl iodide in
10-15 mL THF was prepared separately. The latter solution
was then charged in a 20 mL syringe and mounted to a syringe
pump. The reaction mixture was then heated to 45-50 °C and
the addition of the naphthyl iodide solution started (addition
rate: 2.5-4 mL/h, about 10% of the solution was added
immediately). After completion of the addition, the reaction
mixture was stirred for another 20 h at the same temperature.
After the mixturewas cooled, satdNH4Clsolutionwas added and
the mixturestirredunder argonfor 15 min. The crudemixturewas
filtered over Celite and the filtrate then extracted with ethyl
acetate. The combined organic phases were washed with water
and brine and dried over Na2SO4. After removal of all volatiles
the residue was purified by column chromatography.
1-(1,7-Octadiynyl)-2-benzyloxynaphthalene (31). 1-Iodo-
naphthalen-2-ol (4.00 g, 14.8 mmol) and benzyl bromide
(1.76 mL, 14.8 mmol) were dissolved in acetone (130 mL).
Potassium carbonate (2.04 g, 138.2 mmol) and catalytic NaI
(150 mg, 1.0 mmol) were added to the solution, and the resulting
mixture was heated at reflux for 5 h. The yellow solution became
orange. The mixture was cooled to rt and concentrated to a
volume of about 5 mL. Water was added and the mixture
extracted with ethyl acetate (3 ꢀ 15 mL). The combined organic
layers were dried with Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromato-
graphy (eluent: petroleum ether/ethyl acetate, 9:1 v/v) to yield
1-iodo-2-benzyloxynaphthalene as a syrup (1.65 g, 31%). 1HNMR
(300 MHz, CDCl3): δ = 8.22 (dd, 1H, J = 8.6, 0.9 Hz), 7.78 (d,
1H, J = 8.9 Hz), 7.75 (d, 1H, J = 8.4 Hz), 7.62-7.57 (m, 3H),
7.48-7.39 (m, 4H), 7.21 (d, 1H, J = 8.9 Hz), 5.31 (s, 2H) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.8, 136.7, 135.7, 131.4,
130.3, 130.1, 128.7, 128.3, 128.2, 128.0, 127.3, 124.6, 114.7, 89.1,
71.9 ppm. MS (70 eV) m/z: 360 (45) [Mþ], 233 (29), 114 (19), 91
(100). HRMS (EI) for C17H13OI: calcd 360.0006, found 359.9996.
Diyne 31 was prepared following general procedure 2 using 1-iodo-
2-benzyloxynaphthalene (1.39 g, 3.86 mmol) and 1,7-octadiyne
(1.23 g, 11.57 mmol) as well as Pd(PPh3)4 (0.23 g, 0.19 mmol) as the
catalyst, giving 700 mg (54%) of pure diyne as a substance of
syrupy consistence after chromatography with petroleum ether/
ethyl acetate (19:1 v/v) as the eluent on silica gel. For use in the
cycloaddition reaction the substrate was prepared as follows: 31
was dissolved in dry THF, and active molecular sieves were added
for removal of residual water. After being stirred for a short period,
the solution was filtered, the THF removed under reduced pres-
General note: During workup after the coupling reaction up
to 14% of the diarylated diynes was separated as byproducts
and identified by NMR and MS. However, these data are not
detailed here.
1-(1,7-Octadiynyl)-2-methoxynaphthalene (2)14. Compound 2
was prepared following the general procedure 1 using 1-iodo-2-
methoxynaphthalene (38, 8.52 g, 30 mmol)33 and 1,7-octadiyne
(6.37 g, 60 mmol) to yield 5.28 g (68% yield) of pure product after
chromatography with petroleum ether/ethyl acetate (6:1 v/v) on
silicagel. Mp:60-61 °C(n-hexane). 1H NMR(400MHz, CDCl3):
δ = 8.27 (dd, 1H, J = 8.5, 0.8 Hz), 7.80-7.75 (m, 2H), 7.53 (ddd,
1H, J = 8.5, 6.8, 1.3 Hz), 7.37 (ddd, 1H, J = 8.1, 6.8, 1.2 Hz), 7.23
(d, 1H, J = 9.1 Hz), 4.02 (s, 3H), 2.69 (t, 2H, J = 6.7 Hz), 2.32 (td,
2H, J = 6.7, 2.6 Hz), 2.00 (t, 1H, J = 2.6 Hz), 1.94-1.78 (m, 4H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 135.2, 129.7,
129.0, 128.4, 127.5, 125.8, 124.5, 113.1, 107.4, 100.0, 84.7, 75.5,
68.9, 57.0, 28.4, 28.1, 20.1, 18.5. MS (EI, 70 eV) m/z:262(53) [Mþ],
247 (41), 233 (38), 231 (39), 215 (30), 219 (33), 203 (34), 181 (26),
165 (100), 152 (65), 139 (23). Anal. Calcd for C19H18O (262.35): C,
86.99; H, 6.92. Found: C, 86.90; H, 6.88.
1
sure, and the residue dried in high vacuo. H NMR (300 MHz,
CDCl3):δ=8.28(dd,1H,J= 8.6, 1.1 Hz), 7.76 (d, 1H, J=8.1Hz),
7.72 (d, 1H, J = 9.0 Hz), 7.56-7.50 (m, 3H), 7.42-7.36 (m, 3H),
7.35-7.31 (m, 1H), 7.23 (d, 1H, J = 9.0 Hz), 5.32 (s, 2H), 2.68 (t,
2H, J = 6.7 Hz), 2.26 (td, 2H, J = 6.7, 2.7 Hz), 1.97 (t, 1H, J =
2.6 Hz), 1.89-1.75 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 158.1, 137.4, 134.9, 129.2, 129.0, 128.6, 128.1, 127.9, 127.3,
127.2, 125.6, 124.4, 115.3, 108.6, 99.8, 84.4, 71.7, 68.7, 28.0, 27.7,
19.8, 18.1 ppm. MS (70 eV) m/z: 338 (14) [Mþ], 257 (17), 253 (23),
247 (30), 219 (17), 165 (17), 152 (23), 91 (100). HRMS (EI) for
C25H22O: calcd 338.1665, found 338.1671.
1-(1,7-Octadiynyl)-2-carbomethoxynaphthalene (32). The diyne
was prepared using 1-bromo-2-carbomethoxynaphthalene (6.63 g,
25 mmol)34 and 1,7-octadiyne (5.31 g, 50 mmol) following general
procedure 1, yielding 4.86 g (67%) of product. Mp: 37-38 °C
1-(1,7-Octadiynyl)naphthalene-2-yl Pivalate (30). In a 250 mL
Schlenk flask, 1-iodonaphthalen-2-ol (1.0 g, 6.93 mmol) and
4-dimethylaminopyridine (DMAP, 84.6 mg, 0.69 mmol) were
dissolved in CH2Cl2 (25 mL) and NEt3 (1.2 mL, 8.32 mmol).
Pivaloyl chloride (1.0 mL, 8.31 mmol) was added slowly to the
solution, which was then stirred for 4 h at rt. The reaction was
quenched by addition of NaHSO3 solution and extracted with
CH2Cl2 several times. The combined organic phases were dried
over Na2SO4, and column chromatography on silica with
n-hexane/ethyl acetate (2:1, v/v) as eluent yielded the product
1-iodonaphthalen-2-yl pivalate (1.3 g, 53%), which was directly
used for the next step. 1H NMR (300 MHz, CDCl3): δ = 8.20
(d, 1H, J = 8.5 Hz), 7.82 (d, 1H, J = 8.8 Hz), 7.78 (dd, 1H, J =
8.0, 1.2 Hz), 7.59 (ddd, 1H, J = 8.5, 6.9, 1.4 Hz), 7.50 (ddd, 1H,
€
(34) Weber, E.; Csoregh, I.; Stensland, B.; Czugler, M. J. Am. Chem. Soc.
1984, 106, 3297.
(33) Preparation: Iskra, J.; Stauber, S.; Zupan, M. Synthesis 2004, 1869.
J. Org. Chem. Vol. 75, No. 12, 2010 3999

Hapke et al.
JOCArticle
(pentane). 1H NMR (400 MHz, CDCl3): δ = 8.54 (dd, 1H, J = 7.9,
2.1 Hz), 7.88 (d, 1H, J=8.7Hz), 7.84(dd, 1H, J= 7.4, 1.8 Hz), 7.77
(d,1H,J= 8.7 Hz), 7.62-7.55 (m, 2H), 3.98 (s, 3H), 2.71 (t, 2H, J=
6.8 Hz), 2.31 (td, 2H, J = 6.8, 2.6 Hz), 1.99 (t, 1H, J = 2.6 Hz),
1.91-1.84 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.6,
134.5, 133.9, 130.5, 128.2, 128.1, 127.9, 127.6, 127.4, 125.7, 123.2,
102.1, 84.2, 77.4, 68.7, 52.3, 27.8 (2), 19.2, 18.2 ppm. MS (EI, 70 eV)
m/z: 291 (100) [Mþ], 275 (67), 259 (13), 231 (18). Anal. Calcd for
C20H18O2 (290.36): C, 82.73; H, 6.25. Found: C, 82.70; H, 6.24.
1-(1,7-Octadiynyl)-2-hydroxymethylnaphthalene (33). In a
250 mL Schlenk flask was dissolved diyne 32 (2.0 g, 6.89 mmol)
in toluene and the mixture cooled to 0 °C. Red-Al (2.70 mL, 9.65
mmol, 70% solution) was added slowly, and after complete
addition the mixture was stirred for 19 h at rt. Additional Red-Al
(0.97 mL, 3.42 mmol, 70% solution) was added and the mixture
stirred for another 4 h. The reaction was quenched by addition of
Na2SO4 solution and filtered over Celite. The aqueous phase was
extracted with ethyl acetate, and the combined organic phases
were washed with brine. After drying over Na2SO4, column chro-
matography on silica using petroleum ether/ethyl acetate (6:1, v/v)
as the eluent yielded the product as viscous colorless oil (1.25 g,
69%). For use in the cycloaddition reaction the substrate was
prepared as follows: 33 was dissolved in dry THF, and active
molecular sieves were added for removal of residual water. After
being stirred for a short period, the solution was filtered, the THF
removed under reduced pressure, and the residue dried under high
vacuum. 1H NMR (300 MHz, CDCl3):δ=8.34(d,1H,J=8.3Hz),
7.83 (d, 1H, J = 8.1 Hz), 7.79 (d, 1H, J = 8.5 Hz), 7.57 (d, 1H,
J = 8.5 Hz), 7.57 (ddd, 1H, J = 8.3, 6.7, 1.6 Hz), 7.49 (ddd, 1H,
J = 8.1, 6.7, 1.3 Hz), 5.01 (s, 2H), 2.67 (t, 2H, J = 6.7 Hz), 2.31
(td, 2H, J = 6.7, 2.6 Hz), 2.13 (s, 1H), 2.00 (t, 1H, J = 2.6 Hz),
1.90-1.76 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.0,
133.7, 132.7, 128.2 (2), 126.9, 126.3 (2), 125.4, 119.2, 100.5, 84.2,
76.6, 68.9, 64.6, 28.0, 27.8, 19.6, 18.2ppm. MS(70eV)m/z: 262 (9)
[Mþ], 233(26), 215 (31), 202 (20), 191(100), 178 (29), 165 (70), 152
(42). Anal. Calcd for C19H18O (262.35): C, 86.99; H, 6.92. Found:
C, 87.07; H, 7.35.
1-(1,6-Heptadiynyl)-2-methoxynaphthalene (39). The com-
pound was prepared following general procedure 1 using 1-iodo-
2-methoxynaphthalene (38, 2.84 g, 10 mmol) and 1,6-heptadiyne
(1.85 g, 20 mmol), yielding 1.40 g (56%) of pure product after
chromatography with petroleum ether/ethyl acetate (6:1 v/v) on
silica gel. Mp: 44-45 °C (n-hexane). 1H NMR (300 MHz,
CDCl3): δ = 8.26 (d, 1H, J = 8.5 Hz), 7.75-7.80 (m, 2H), 7.54
(ddd, 1H, J = 8.5, 6.8, 1.2 Hz), 7.37 (ddd, 1H, J = 8.2, 6.8,
1.2 Hz), 7.23 (d, 1H, J = 9.1 Hz), 4.02 (s, 3H), 2.79 (t, 2H, J =
7.0 Hz), 2.50 (dt, 2H, J = 7.1, 2.7 Hz), 2.03 (t, 1H, J = 2.4 Hz),
1.98 (t, 2H, J = 7.0 Hz) ppm. 13C NMR (75 MHz, CDCl3): δ =
158.8, 134.9, 129.5, 128.6, 128.1, 127.3, 125.4, 124.2, 112.8, 106.9,
98.9, 83.8, 75.5, 69.0, 56.7, 28.0, 19.4, 17.9 ppm. MS (70 eV) m/z:
248 (10) [Mþ], 233 (30), 217 (45), 202 (53), 189 (25), 181 (21), 165
(60), 152 (76), 139 (30), 115 (19), 39 (22). Anal. Calcd for C18H16O
(248.32): C, 87.06; H, 6.49. Found: C, 87.13; H, 6.40.
73.2, 56.6, 46.1, 44.8, 41.5 ppm. MS (EI, 70 eV) m/z: 263 (11)
[Mþ], 262 (21) [M - H]þ, 248 (20), 220 (100), 195 (19), 165 (39),
152 (50). Anal. Calcd for C18H17NO (263.33): C 82.10, H 6.51, N
5.32. Found: C 82.18, H 6.60, N 5.07.
1-(3-(Prop-2-ynyloxy)prop-1-ynyl)-2-methoxynaphthalene (41).
Diyne 41 was prepared following general procedure 2, using 1-iodo-
2-methoxynaphthalene (38, 4 g, 14.1 mmol) and dipropargyl ether
(2.65 g, 28.2 mmol) as well as Pd(PPh3)4 as the catalyst, giving 1.22 g
(35%) of pure diyne after chromatography with petroleum ether/
ethyl acetate (6:1 v/v) on silica gel. Mp: 62-63 °C. 1H NMR (400
MHz, CDCl3): δ = 8.26 (d, 1H, J = 8.5 Hz), 7.82 (d, 1H, J = 9.1
Hz), 7.78 (d, 1H, J = 8.1 Hz), 7.55 (ddd, 1H, J = 8.5, 6.8, 1.3 Hz),
7.38 (ddd, 1H, J= 8.1, 6.8, 1.2 Hz), 7.23 (d, 1H, J=9.1Hz), 4.73 (s,
3H), 4.46 (d, 1H, J = 2.4Hz), 4.01 (s, 3H), 2.52 (t,1H, J = 2.4Hz)
ppm. 13C NMR (100 MHz, CDCl3): δ = 159.4, 134.7, 130.5,
128.5, 128.2, 127.5, 125.2, 124.3, 112.6, 105.5, 93.7, 81.5, 79.3,
75.0, 57.9, 56.6, 56.5 ppm. MS (EI, 70 eV) m/z: 250 (78) [Mþ], 221
(35), 220 (71), 219 (32), 195 (25), 191 (33), 189 (28), 181 (34), 169
(26), 165 (74), 152 (100), 151 (46), 139 (69). Anal. Calcd for C17
14O2 (250.29): C, 81.58; H, 5.64. Found: C, 81.37; H, 5.67.
1-(1,8-Nonadiynyl)-2-methoxynaphthalene (42). Diyne 42 was
-
H
prepared following general procedure 2, using 1-iodo-2-meth-
oxynaphthalene (38, 2 g, 7.04 mmol) and 1,8-nonadiyne (1.69 g,
14.1 mmol) as well as Pd2dba3 CHCl3 and dppf as the catalyst
3
system (addition rate of the napthyl iodide solution: 2 mL/h for
1 h, then 0.15 mL/h), giving 1.07 g (55%) pure diyne as an oil
that solidifies on standing after chromatography with petroleum
ether/ethyl acetate (6:1 v/v) on silica gel. Mp: 52-54 °C(n-hexane).
1H NMR (400 MHz, CDCl3): δ = 8.27 (d, 1H, J = 8.5 Hz), 7.77
(d, 1H, J = 8.7 Hz), 7.77 (d, 1H, J = 8.5 Hz), 7.53 (ddd, 1H, J =
8.5, 6.8, 1.3 Hz), 7.37 (ddd, 1H, J = 8.5, 6.8, 1.2 Hz), 7.24 (d, 1H,
J = 8.7 Hz), 4.02 (s, 3H), 2.67 (t, 2H, J = 6.8 Hz), 2.25 (td, 2H,
J = 6.6, 2.6Hz), 1.96 (t, 1H, J =2.6Hz), 1.82-1.60 (m, 6H) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.7, 134.9, 129.3, 128.7,
128.1, 127.2, 125.5, 124.1, 112.8, 107.1, 100.1, 84.6, 75.0, 68.5,
56.8, 28.7, 28.3, 28.2, 20.2, 18.5 ppm. MS (EI, 70 eV) m/z: 276
[Mþ] (57), 261 (20), 245 (23), 233 (24), 217 (20), 203 (22), 195 (43),
181 (25), 165 (100), 152 (73). Anal. Calcd for C20H20O (276.37):
C, 86.92; H, 7.29. Found: C, 86.99; H, 7.34.
1-(1,9-Decadiynyl)-2-methoxynaphthalene (43). Compound
43 was synthesized following general procedure 2, using 1-iodo-
2-methoxynaphthalene (38, 2 g, 7.04 mmol) and 1,9-decadiyne
(1.89 g, 14.1 mmol) as well as Pd2dba3 CHCl3 and dppf as
3
the catalyst system (addition rate of the napthyl iodide solution:
2 mL/h for 1 h, then 0.15 mL/h), giving 1.20 g (59%) pure diyne as
an oil after chromatography with petroleum ether/ethyl acetate
(6:1 v/v) on silica gel. 1H NMR (400 MHz, CDCl3): δ = 8.26 (d,
1H, J = 8.5 Hz), 7.77 (d, 1H, J= 9.1 Hz), 7.77 (d, 1H, J= 8.2 Hz),
7.52 (ddd, 1H, J = 8.5, 6.8, 1.2 Hz), 7.36 (ddd, 1H, J = 8.2, 6.8,
1.2 Hz), 7.24 (d, 1H, J = 9.1 Hz), 4.02 (s, 3H), 2.65 (t, 2H, J =
7.0 Hz), 2.30-2.15 (m, 2H), 1.95 (t, 1H, J = 2.6 Hz), 1.81-1.71
(m, 2H), 1.64-1.47 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3):
δ= 158.7, 135.0, 129.3, 128.7, 128.1, 127.2, 125.5, 124.2, 112.9, 107.2,
100.3, 84.8, 74.9, 68.5, 56.8, 29.0, 28.6 (2), 28.5, 20.3, 18.5 ppm. MS
(EI,70eV) m/z: 291 (44) [Mþ],195(41),181(20),165(100),152(64).
HRMS (EI) for C21H23O: calcd 291.1743, found 291.1741.
1-(3-(Prop-2-ynyl(methyl)amino)prop-1-ynyl)-2-methoxy-
naphthalene (40). The compound was prepared from 1-iodo-
2-methoxynaphthalene (38, 8.64 g, 30 mmol) and N-methyl-
N,N-dipropargylamine (5.36 g, 50 mmol)35 following general
procedure 1, yielding 5.21 g (66%) of product after column
chromatography (eluent: diethyl ether/n-hexane, 10:1 v/v). Mp:
76-77°C (n-hexane). 1H NMR(400 MHz, CDCl3):δ= 8.27 (dd,
1H, J = 8.5, 1.2Hz), 7.79 (d, 1H, J = 9.1Hz), 7.77 (d, 1H, J = 8.2
Hz), 7.54 (ddd, 1H, J = 8.5, 6.8, 1.3 Hz), 7.37 (ddd, 1H, J = 8.2,
6.8, 1.2 Hz), 7.22 (d, 1H, J = 9.1 Hz), 4.00 (s, 3H), 3.83 (s, 2H),
3.56 (t, 1H, J = 2.4 Hz), 2.55 (s, 3H), 2.31 (d, 2H, J = 2.4 Hz)
ppm. 13C NMR (100 MHz, CDCl3): δ = 159.2, 134.7, 130.0,
128.6, 128.1, 127.4, 125.3, 124.2, 112.8, 106.3, 94.0, 79.8, 79.3,
General Procedure for the Enantioselective [2 þ 2 þ 2] Co-
cyclotrimerization. An inerted and thermostated (for the corres-
ponding temperature refer to Tables 2 and 3) reaction vessel was
loaded with either diyne 2, 30-33, or 39-43 (2 mmol), catalyst
1b (0.02-0.1 mmol), THF (20 mL), and nitrile (2.5-6 mmol)
under argon atmosphere. The mixture was stirred thoroughly
and irradiated by two 460 W lamps (λ ≈ 420 nm) for 24-72 h.
The reaction was quenched by switching off the lamps and
opening the reaction vessel to air. The solvent was evaporated,
and the oily residue was purified on silica using n-hexane-Et2O
or n-hexane-ethyl acetate in different proportions as eluent.
Further purification was done by recrystallization.
(35) Iwai, I.; Yura, Y. Chem. Pharm. Bull. 1963, 11, 1049.
4000 J. Org. Chem. Vol. 75, No. 12, 2010

Hapke et al.
JOCArticle
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-phenyl-5,6,7,8-tetrahydro-
(s, 1H), 7.38 (d, 1H, J = 9.1 Hz), 7.35-7.31 (m, 2H), 7.26-7.22
(m, 1H), 7.21 (s, 2H), 3.90 (s, 6H), 3.88 (s, 3H), 3.87 (s, 3H), 2.9 (t,
2H, J = 5.8 Hz), 2.48 (dd, 1H, J = -16.9, 6.6 Hz), 2.23 (dd, 1H,
J = -16.9, 5.6 Hz), 1.88-1.79 (m, 2H), 1.77-1.63 (m, 2H) ppm.
13C NMR (75 MHz, CDCl3): δ = 154.2, 153.5, 153.4, 147.7,
138.8, 133.1, 132.3, 130.1, 129.2, 128.1, 126.7, 124.5, 123.6, 120.5,
113.7, 104.8 (2), 61.0, 56.7, 56.3, 29.9, 25.5, 22.8, 22.3 ppm (not all
quaternary carbons could be assigned to individual peaks; given
are the most clearly resolved signals). MS (70 eV) m/z: 455 (100)
[Mþ], 440 (20), 436 (25), 424 (19), 227 (12). Anal. Calcd for
C29H29NO4 (455.54): C, 76.46; H, 6.42; N, 3.07. Found: C, 76.59;
H, 6.55; N, 3.05.
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-(2,3,4-trimethoxyphenyl)-
5,6,7,8-tetrahydroisoquinoline (21). Following the general proce-
dure, compound 21 was obtained from 2 (525 mg, 2 mmol) and
2,3,4-trimethoxybenzonitrile (11, 502 mg, 2.6 mmol) with a yield
of 401 mg (44%) as a solid foam. [R]25D =þ132.2 (c=0.8,CHCl3).
Enantiomeric purity by HPLC analysis 94% ee. HPLC condi-
tions: Chiracel OD-H, n-hexane/ethanol 99:1, 1.0 mL/min, T1 =
12.94 min, T2 = 14.06 min. 1H NMR (400 MHz, CDCl3): δ =
7.93 (d, 1H, J = 9.0 Hz), 7.85-7.82 (m, 1H), 7.57 (s, 1H), 7.48 (d,
1H, J = 8.7 Hz), 7.38 (d, 1H, J = 9.0 Hz), 7.37-7.31 (m, 2H),
6.23 (d, 1H, J = 8.6 Hz), 6.73 (d, 1H, J = 8.7 Hz), 3.92 (s, 3H),
3.86 (s, 3H), 3.86 (2 s, 6H), 2.96 (t, 2H, J = 5.8 Hz), 2.47 (dd, 1H,
J = -17.2, 6.5 Hz), 2.24 (dd, 1H, J = -17.2, 5.8 Hz), 1.88-1.80
(m, 2H), 1.79-1.72 (m, 1H), 1.72-1.64 (m, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.4, 154.6, 154.3, 152.5, 151.9, 146.4,
142.4, 133.4, 131.5, 129.6, 129.2, 128.2, 128.0, 126.8, 126.0, 125.2,
124.6, 124.5, 123.7, 113.8, 107.7, 61.6, 61.1, 56.8, 56.2, 29.9, 25.5,
22.8, 22.3 ppm. MS (70 eV) m/z: 455 (48) [Mþ], 440 (100), 424
(15), 408 (24). Anal. Calcd for C29H29NO4 (455.54): C, 76.46; H,
6.42; N, 3.07. Found: C, 76.59; H, 6.88; N, 2.55.
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-(4-trifluoromethylphenyl)-
5,6,7,8-tetrahydroisoquinoline (22). Diyne 2 (525 mg, 2 mmol) and
4-trifluoromethylbenzonitrile (12, 684 mg, 4 mmol) were reacted
following the general procedure to yield 22 as an off-white solid
(511 mg, 59%). Mp: 158-159 °C(Et2O/n-hexane). [R]25D =þ148.9
(c = 0.1, CHCl3). Enantiomeric purity by HPLC analysis 86% ee
(HPLC conditions: Chiralpak AD-H, n-hexane/ethanol 98:2,
1.0 mL/min, T1 = 5.73 min, T2 = 6.96 min). 1H NMR (300 MHz,
CDCl3): δ = 8.13 (d, 2H, J = 8.2 Hz), 8.96 (d, 1H, J = 9.1 Hz),
7.89-7.84 (m, 1H), 7.67 (d, 2H, J = 8.2 Hz), 7.57 (s, 1H), 7.40 (d,
1H, J = 9.1 Hz), 7.38-7.33 (m, 2H), 7.26-7.20 (m, 1H), 3.90 (s,
3H), 2.98 (t, 2H, J = 6.1 Hz), 2.51 (dd, 1H, J = -17.5, 6.6 Hz),
2.25 (dd, 1H, J = -17.5, 6.0 Hz), 1.91-1.81 (m, 2H), 1.81-1.64
(m, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.8, 154.2,
152.2, 148.2, 142.5, 133.6, 133.1, 130.6, 130.3 (2), 129.3, 128.2,
127.7, 126.9, 125.6 (q, 3JC-F = 3.7 Hz), 124.7 (q, 1JC-F = 272
Hz), 124.4, 123.8, 121.2, 113.7, 56.8, 29.9, 25.6, 22.8, 22.3 ppm.
19F NMR (282 MHz, CDCl3): δ = 62.0 ppm. MS (70 eV) m/z:
433 (75) [Mþ], 432 (100), 414 (51), 402 (27), 389 (23). Anal. Calcd
for C27H22F3NO (433.46): C, 74.81; H, 5.12; N, 3.23. Found: C,
75.19; H, 5.54; N, 3.10.
isoquinoline (6)14a. Mp: 200-201 °C (ethyl acetate). [R]25
=
D
þ202.5 (c = 0.1, toluene). Enantiomeric purity by HPLC analysis
>98% ee. HPLC conditions: Chiralpak AD-H, n-hexane/ethanol
99:1, 1.0 mL/min, T1 = 6.67 min, T2 = 8.31 min. 1H NMR
(400 MHz, CDCl3): δ = 8.09-8.06 (m, 2H), 7.97 (d, 1H, J =
9.0 Hz), 7.92-7.87 (m, 1H), 7.58 (s, 1H), 7.50-7.44 (m, 2H),
7.44-7.37 (m, 5H), 3.91 (s, 3H), 2.98 (td, 2H, J = 6.1, 2.8 Hz), 2.57
(ddd, 1H, J = -17.4, 7.7, 6.1 Hz), 2.27 (dd, 1H, J = -17.4,
0.0 Hz), 1.92-1.84 (m, 2H), 1.84-1.77 (m, 1H), 1.75-1.66 (m, 1H)
ppm. 13C NMR (100 MHz, CDCl3):δ= 155.8, 154.1, 153.9, 146.9,
140.1, 133.3, 132.0, 129.7, 129.3, 128.5, 128.2, 128.0, 127.1, 126.5,
124.8, 123.8, 123.6, 120.2, 113.8, 56.7, 29.7, 25.5, 23.0, 22.4 ppm.
MS (70 eV) m/z: 365 (72) [Mþ], 364 (100), 346 (40), 334 (27), 321
(18), 306 (6). Anal. Calcd for C26H23NO (365.47) 0.5H2O (18.02):
3
C, 83.39; H, 6.46; N, 3.74. Found: C, 83.46; H, 6.55; N, 3.13.
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-methyl-5,6,7,8-tetrahydro-
isoquinoline (7)14a. Following the general procedure, biaryl 7 was
obtained from 2 (525 mg, 2 mmol) and acetonitrile (4, 314 μL,
6 mmol) as a solid with a yield of 398 mg (66%). Mp: 160-161 °C
(pentane). [R]25 = þ138.9 (c = 0.1, toluene). Enantiomeric
D
purity after recrystallization by HPLC analysis >98% ee (HPLC
conditions: Chiralcel OD-H, n-hexane/ethanol 99.95:0.05, 1.5 mL/
min, T1 = 4.72 min, T2 = 5.94 min). 1H NMR (400 MHz, CDCl3):
δ = 7.89 (d, 1H, J = 9.0 Hz), 7.83-7.79 (m, 1H), 7.36 (d, 1H, J =
9.0 Hz), 7.34-7.29 (m, 2H), 7.18-7.13 (m, 1H), 6.95 (s, 1H), 3.86
(s, 3H), 2.82 (t, 2H, J = 6.3 Hz), 2.57 (s, 3H), 2.40 (dd, 1H, J =
-17.3, 6.4 Hz), 2.14 (dd, 1H, J = -17.3, 6.1 Hz), 1.81-1.74
(m, 2H), 1.74-1.66 (m, 1H), 1.66-1.58 (m, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.1, 154.4, 153.8, 146.6, 133.2,
130.0, 129.6, 129.3, 127.9, 126.5, 124.6, 123.6, 123.5, 122.7,
113.6, 56.6, 29.4, 25.3, 24.2, 23.0, 22.4 ppm. MS (70 eV) m/z:
303 (74) [Mþ], 302 (100), 284 (57), 272 (38), 259 (24). Anal.
Calcd for C21H21NO (303.40): C, 83.13; H, 6.98; N, 4.62.
Found: C, 83.05; H, 7.14; N, 4.50.
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-tert-butyl-5,6,7,8-tetra-
hydroisoquinoline (8)14a. Following the general procedure, biaryl
8 was obtained from 2 (525 mg, 2 mmol) and tert-butylnitrile
(5, 442 μL, 4 mmol) with a yield of 547 mg (79%) as a solid. Mp:
106-107 °C (n-hexane). [R]25 = þ205.2 (c = 0.1, toluene).
D
Enantiomeric purity after recrystallization by HPLC analysis
>98% ee (HPLC conditions: Chiralcel OD-H, n-hexane/2-pro-
panol 99.95:0.05, 1.0 mL/min, T1 = 9.42 min, T2 = 10.95 min).
1H NMR (300 MHz, CDCl3): δ = 7.92 (d, 1H, J = 9.0 Hz),
7.86-7.82 (m, 1H), 7.39 (d, 1H, J = 9.0 Hz), 7.35-7.31 (m, 2H),
7.18-7.13 (m, 2H), 3.88 (s, 3H), 2.89(t, 2H, J = 6.3 Hz), 2.41 (dd,
1H, J = -17.1, 6.6 Hz), 2.12 (dd, 1H, J = -17.1, 6.1 Hz), 1.85-
1.75 (m, 2H), 1.75-1.56 (m, 2H), 1.44 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.2, 154.2, 146.1, 145.7, 133.3, 129.8,
129.5, 128.0, 126.5, 126.2, 124.8, 123.7, 118.3, 114.6, 57.3, 37.0,
30.4, 29.9, 25.3, 23.0, 22.5 ppm (one quaternary carbon could
not be assigned). MS (70 eV) m/z: 345 (100) [Mþ], 330 (72), 314
(29), 303 (72). Anal. Calcd for C24H27NO (345.48): C, 83.44; H,
7.88; N, 4.05. Found: C, 83.42; H, 7.96; N, 3.69.
(R)-1-(2-Methoxy-1-naphthyl)-3-(4-dimethylaminophenyl)-5,6,7,8-
tetrahydroisoquinoline (23). When the general procedure was fol-
lowed at a reaction temperature of -10 °C instead of -20 °C, biaryl
23 was obtained from diyne 2 (142 mg, 0.54 mmol) and 4-dimethyl-
aminobenzonitrile (13, 158 mg, 1.08 mmol) with a yield of 127 mg
(58%) as a white solid. Mp: 209-210 °C. Enantiomeric purity by
HPLC analysis 83% ee (for the reaction at -10 °C). HPLC con-
ditions: Chiralpak AD-H, n-heptane/ethanol 95:5, 1.0 mL/min,
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-(3,4,5-trimethoxyphenyl)-
5,6,7,8-tetrahydroisoquinoline (20)36. Diyne 2 (788 mg, 3 mmol)
and 3,4,5-trimethoxybenzonitrile (10, 753 mg, 3.9 mmol) were
reacted according to the general procedure to give compound
20 after column chromatography with 875 mg (64%) yield.
Mp: 140-141 °C (benzene/n-hexane). [R]25 = þ173.2 (c =
D
0.3, CHCl3). Enantiomeric purity by HPLC analysis: 91% ee
(HPLC conditions: Chiralpak AD, n-hexane/ethanol 95:5, 1.0
mL/min, T1 = 13.8 min, T2 = 19.8 min). 1H NMR (400 MHz,
CDCl3): δ = 7.94 (d, 1H, J = 9.1 Hz), 7.86-7.81 (m, 1H), 7.47
1
T1 = 4.37 min, T2 = 11.48 min. H NMR (400 MHz, CDCl3):
δ = 7.94-7.90 (m, 3H), 7.86-7.82 (m, 1H), 7.45 (s, 1H), 7.38 (d,
1H, J = 9.0 Hz), 7.36-7.30 (m, 3H), 6.82 (d, 2H, J = 9.0 Hz), 3.87
(s, 3H), 2.98 (s, 6H), 2.92 (t, 2H, J = 6.5 Hz), 2.47 (ddd, 1H,
J = -17.2, 7.6, 5.8 Hz), 2.17 (dd, 1H, J = -17.2, 6.0 Hz),
1.86-1.78 (m, 2H), 1.78-1.70 (m, 1H), 1.69-1.60 (m, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.3, 154.2, 154.0, 150.7,
(36) Preliminary data: Malkov, A. V.; Westwater, M.-M.; Gutnov, A.;
ꢀ
ꢀ
ꢀ
ꢁ
ꢀ
Ramırez-Lopez, P.; Friscourt, F.; Kadlcıkova, A.; Hodacova, J.; Rankovic,
ꢁ
Z.; Kotora, M.; Kocovsky, P. Tetrahedron 2008, 64, 11335.
ꢀ
J. Org. Chem. Vol. 75, No. 12, 2010 4001

Hapke et al.
JOCArticle
146.8, 133.5, 133.4, 130.6, 129.6, 129.4, 128.2, 127.9, 126.5,
125.0, 124.1, 123.6, 119.0, 114.1, 112.4, 56.9, 40.6, 29.8, 25.5,
23.1, 22.6 ppm. MS (EI, 70 eV) m/z: 409 (28), 408 [Mþ] (100),
407 (64), 389 (18), 377 (24), 364 (13), 188 (15). Anal. Calcd for
C28H28N2O (408.53): C, 82.32; H, 6.91; N, 6.86. Found: C,
82.51; H, 7.04; N, 6.97.
min. 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, 1H, J = 9.0 Hz),
7.79-7.83 (m, 1H), 7.36 (d, 1H, J = 9.0 Hz), 7.33-7.31 (m, 3H),
6.50 (s, 1H), 3.87 (s, 3H), 3.49-3.44 (m, 4H), 2.81 (t, 2H, J =
6.4 Hz), 2.52 (ddd, 1H, J = -16.5, 7.8, 5.6 Hz), 2.03 (dd, 1H, J =
-16.5, 6.3 Hz), 1.79-1.71 (m, 2H), 1.68-1.56 (m, 8H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 158.2, 153.9, 153.3, 147.6, 133.3,
129.4, 129.2, 127.9, 126.3, 125.2, 124.8, 123.5, 122.6, 114.4, 106.3,
57.1, 47.2, 30.2, 25.6, 25.0, 24.9, 23.6, 22.9 ppm. MS (EI, 70 eV)
m/z: 372 (100) [Mþ], 343 (91), 329 (26), 316 (67), 289 (69). HRMS
(EI) for C25H28N2O1: calcd 372.2196, found 372.2189. Anal.
Calcd for the picrate salt, C31H31N5O8 (601.61): C, 61.89; H,
5.19; N, 11.64. Found: C, 61.44; H, 5.18; N, 11.69.
1-(3-Phenyl-5,6,7,8-tetrahydro-1-isoquinolinyl)naphthalen-2-yl
Pivalate (34). When diyne 30 (200mg, 0.6mmol) andbenzonitrile
(3, 120 μl, 1.2 mmol) were reacted according to the general
procedure, compound 34 was isolated after column chromato-
graphy with 30 mg (11%) yield. Enantiomeric excess by HPLC
analysis 52% ee. HPLC conditions: Chiracel OD-H, n-heptane/
ethanol 98:2, 0.3 mL/min, T1 = 10.01 min, T2 = 11.12 min. 1H
NMR (300 MHz, CDCl3): δ = 7.99-7.88 (m, 4H), 7.50 (s, 1H),
7.51-7.33 (m, 7H), 2.96-2.86 (m, 2H), 2.40 (ddd, 1H, J =
-17.4, 6.3, 6.3), 2.20 (ddd, 1H, J = -17.4, 6.3, 6.3), 1.85-1.75
(m, 2H), 1.72-1.64 (m, 2H), 0.98 (s, 9H) ppm. 13CNMR(75MHz,
CDCl3): δ = 177.0, 154.3, 146.2, 135.9, 132.6, 132.1, 131.9, 129.3,
128.7, 128.5, 128.3, 127.2, 126.8, 125.7, 125.6 (2), 122.2, 120.5, 39.0,
29.9, 26.9, 25.7, 23.1, 22.6 ppm. MS (70 eV) m/z: 435 (29) [Mþ], 350
(100), 322 (12). HRMS (ESI) for C30H30NO2: calcd 436.2271,
found 436.2275.
1-(2-Methoxy-1-naphthyl)-3-(4-chlorophenyl)-5,6,7,8-tetra-
hydroisoquinoline (24). Diyne 2 (393.5 mg, 1.5 mmol) and 4-chloro-
benzonitrile (14, 413 mg, 3 mmol) were reacted according to the
general procedure to give compound 24 after column chromato-
graphy with 60 mg (10%) yield. 1H NMR (500 MHz, CDCl3): δ =
7.94-7.89 (m, 3H), 7.85-7.81 (m, 1H), 7.47 (s, 1H), 7.38-7.30 (m,
5H), 7.23-7.18 (m, 1H), 3.87 (s, 3H), 2.96-2.90 (m, 2H), 2.46
(ddd, 1H,J=-17.4, 7.9, 6.7 Hz), 2.19 (dd, 1H, J=-17.4, 6.0 Hz),
1.85-1.79 (m, 2H), 1.77-1.70 (m, 1H), 1.69-1.60 (m, 1H) ppm.
13C NMR (125 MHz, CDCl3): δ = 155.4, 154.3, 152.3, 148.6,
134.9, 133.1, 130.4, 129.3, 128.9 (2), 128.3, 126.9, 124.4, 123.8,
120.9, 113.8, 56.9, 30.0, 25.5, 22.8, 22.3 ppm (not all expected
signals were found due to low intensity of quarternary carbons).
MS (ESI) m/z: 400 [MHþ] (100). HRMS (ESI): for C26H22ClNO
calcd 399.1390, found 399.1391.
(R)-1-(2-Methoxy-1-naphthyl)-3-(1-phenyl-4-yl-4,4,5,5-tetramethyl-
1,3-dioxa-2-borolane)-5,6,7,8-tetrahydroisoquinoline (25). Diyne 2
(262 mg, 1 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-
benzonitrile (15, 300 mg, 1.3 mmol) were reacted following the general
procedure to yield 25 as a nearly colorless solid (220 mg, 45%). Mp:
226-228 °C. Enantiomeric purity by HPLC analysis 75% ee. HPLC
conditions: R,R-Whelk, n-heptane/ethanol 98:2, 0.8 mL/min, T1 =
9.33 min, T2 = 10.65 min. 1H NMR (500 MHz, CDCl3):δ=8.01(d,
2H, J = 8.2 Hz), 7.94 (d, 1H, J = 9.1 Hz), 7.86 (d, 2H, J = 8.2 Hz),
7.85-7.82 (m, 1H), 7.56 (s, 1H), 7.38 (d, 1H, J = 9.1 Hz), 7.35-7.32
(m, 2H), 7.24-7.20 (m, 1H), 3.88 (s, 3H), 2.99-2.92 (m, 2H), 2.46
(ddd, 1H, J = -17.4, 7.7, 6.7 Hz), 2.21 (dd, 1H, J = -17.4, 5.9 Hz),
1.86-1.80 (m, 2H), 1.77-1.71 (m, 1H), 1.69-1.63 (m, 1H), 1.35 (s,
12H) ppm. 13C NMR (125 MHz, CDCl3): δ = 154.4, 153.2, 135.2,
133.1, 130.4, 129.3, 128.3, 126.9 (2), 124.4, 123.8, 121.3, 113.9, 83.9,
57.0, 30.0, 25.5, 25.0, 22.8, 22.3 ppm (not all expected signals were
found due to low intensity of quarternary carbons). 11B NMR (160
MHz, CDCl3): δ = 30.9 ppm. MS (ESI) m/z: 492 (100) [MHþ].
Anal. Calcd for C32H34BNO3 (491.43): C, 78.21; H, 6.97; N, 2.85.
Found: C, 78.03; H, 6.96; N, 2.50.
1-(2-Benzyloxy-1-naphthyl)-3-phenyl-5,6,7,8-tetrahydroisoquino-
line (35). When diyne 31 (345 mg, 1.02 mmol) and benzonitrile
(3, 260 μl, 2.04 mmol) were reacted according to the general
procedure, compound 35 was isolated after column chromato-
graphy with 42 mg (9%) yield. Enantiomeric excess by HPLC
analysis 22% ee (reaction at -20 °C) and 55% ee (reaction at
3 °C). HPLC conditions: Reprosil 100, n-heptane/ethanol 98:2,
0.5 mL/min, T1 = 11.34 min, T2 =13.44min. 1H NMR (300 MHz,
CDCl3): δ = 8.06-8.02 (m, 2H), 7.90 (d, 1H, J = 9.1 Hz), 7.88-
7.84 (m, 1H), 7.70-7.57 (m, 2H), 7.55 (s, 1H), 7.51-7.34 (m, 10H),
5.19 (s, 2H), 2.96 (t, 2H, J=6.3Hz), 2.54(ddd, 1H, J=-17.3, 6.6,
6.6 Hz), 2.25 (ddd, 1H, J = -17.3, 6.8, 6.1 Hz), 1.86-1.78 (m, 2H),
1.75-1.65 (m, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.8,
154.0, 153.3, 147.0, 140.2, 137.7, 133.3, 132.9, 132.2, 129.7, 129.6,
129.2, 128.6, 128.4, 128.3, 128.0, 127.6, 127.1, 127.0, 126.6, 123.9,
120.2, 116.2, 71.8, 29.8, 25.7, 23.0, 22.5 ppm. MS (70 eV) m/z: 440
(74) [M - H]þ, 424 (44), 350 (100), 334 (45), 322 (20), 91 (37).
HRMS (ESI) for C32H28NO: calcd 442.2165, found 442.2171.
(þ)-(R)-Methyl 1-(3-Phenyl-5,6,7,8-tetrahydro-1-isoquinolinyl)-
2-naphthoate (36). Diyne 32 (581 mg, 2 mmol) and benzonitrile
(3, 618 μL, 6 mmol) were reacted following the general proce-
dure to yield 36 as a white solid (509 mg, 65%). Mp: 161-162 °C
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-(2-furyl)-5,6,7,8-tetra-
hydroisoquinoline (26)36. Following the general procedure 26
was obtained from 2 (1.05 g, 4 mmol) and 2-furonitrile (16,
620 μL, 7 mmol) as a solid with a yield of 1.15 g (81%). Mp:
198-199 °C (acetone). [R]25 = þ172.5 (c = 0.31, CHCl3).
D
Enantiomeric purity by HPLC analysis >98% ee. HPLC
conditions: Chiracel OD-H, n-hexane/ethanol 99:1, 1.0 mL/
min, T1 =5.76min, T2 =7.94 min. 1H NMR (400 MHz, CDCl3):
δ = 7.94 (d, 1H, J = 9.0 Hz), 7.85-7.82 (m, 1H), 7.55 (s, 1H),
7.51 (d, 1H, J = 1.7 Hz), 7.38 (d, 1H, J = 9.0 Hz), 7.36-7.31 (m,
2H), 7.22-7.18 (m, 1H), 6.97 (d, 1H, J = 3.2 Hz), 6.49 (dd, 1H,
J = 3.2, 1.7 Hz), 3.89 (s, 3H), 3.19 (t, 2H, J = 6.3 Hz), 2.41 (dd,
1H, J = -17.5, 6.6 Hz), 2.17 (dd, 1H, J = -17.5, 6.1 Hz),
1.86-1.78 (m, 2H), 1.77-1.69 (m, 1H), 1.69-1.60 (m, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.9, 154.8, 154.0, 146.9,
146.4, 142.6, 133.3, 132.1, 129.8, 129.4, 128.5, 128.0, 126.6, 124.8,
123.6, 118.3, 113.9, 111.8, 107.8, 56.9, 29.8, 25.7, 23.0, 22.4 ppm.
MS (EI, 70 eV) m/z: 355 (70) [Mþ], 354 (100), 336 (43), 326 (25),
324 (27), 311 (20). Anal. Calcd for C24H21NO2 (355.43): C, 81.10;
H, 5.96; N, 3.94. Found: C, 81.10; H, 5.89; N, 3.61.
(n-hexane). [R]25 = þ57.4 (c = 0.7, in CHCl3). Enantiomeric
D
purity by HPLC analysis 87% ee. HPLC conditions: Chiralpak
AD-H, n-hexane/ethanol 99:1, 1.0 mL/min, T1 = 9.9 min, T2 =
1
13.9 min. H NMR (400 MHz, CDCl3): δ = 8.13 (d, 1H, J =
8.7 Hz), 7.99-7.91 (m, 3H), 7.97 (d, 1H, J = 8.7 Hz), 7.56 (ddd,
1H, J = 8.6, 6.8, 1.3 Hz), 7.55 (s, 1H), 7.45-7.32 (m, 5H), 3.70 (s,
3H), 3.02-2.93 (m, 2H), 2.34 (ddd, 1H, J = -17.3, 6.9, 6.5 Hz),
2.16 (dd, 1H, J = -17.3, 6.2 Hz), 1.88-1.80 (m, 2H), 1.78-1.61
(m, 2H) ppm. 13C NMR(100 MHz, CDCl3):δ167.5, 157.8, 153.9,
146.4, 141.5, 140.1, 135.4, 131.9, 131.0, 128.6, 128.3, 128.2 (2),
127.8, 127.2, 127.1, 127.0, 126.8, 126.1, 120.2, 52.2, 29.7, 26.0,
23.0, 22.5 ppm. MS (EI, 70 eV) m/z: 393 (47) [Mþ], 360 (57), 334
(100). Anal. Calcd for C27H23NO2: C, 82.42; H, 5.89; N, 3.56.
Found: C, 82.34; H, 5.80; N, 3.52.
(þ)-(R)-1-(2-Methoxy-1-naphthyl)-3-(1-piperidinyl)-5,6,7,8-
tetrahydroisoquinoline (29). Diyne 2 (262 mg, 1 mmol) and
piperidine-1-carbonitrile (19, 220 mg, 2 mmol) were reacted
following the general procedure to yield 29 as an oil (332 mg,
89%). [R]25D = þ131.2 (c = 0.1, in CHCl3). Enantiomeric purity
by HPLC analysis 86% ee; HPLC conditions: Chiralpak AD-H,
n-hexane/ethanol 99:1, 1.0 mL/min, T1 = 6.26 min, T2 = 9.58
1-(3-Phenyl-5,6,7,8-tetrahydro-1-isoquinolinyl)naphthalene-2-
ylmethanol (37). When diyne 33 (207 mg, 0.79 mmol) and
benzonitrile (3, 0.02 mL, 1.58 mmol) were reacted according
to the general procedure, compound 37 was isolated after
4002 J. Org. Chem. Vol. 75, No. 12, 2010

Hapke et al.
JOCArticle
column chromatography with 59 mg (20%) yield. Enantiomeric
purity by HPLC analysis 35% ee. HPLC conditions: Chiralpak
AD-H, n-heptane/ethanol 95:5, 1.0 mL/min, T1 = 9.78 min,
T2 = 12.21 min. 1H NMR (300 MHz, CDCl3): δ = 7.98-7.89
(m, 4H), 7.66 (d, 1H, J = 8.4 Hz), 7.60 (s, 1H), 7.47 (ddd, 1H,
J = 8.1, 6.4, 1.7 Hz), 7.44-7.35 (m, 5H), 4.41 (s, 2H), 3.02-2.94
(m, 2H), 2.35 (ddd, 1H, J = -17.4, 8.1, 5.8 Hz), 2.13 (dd, 1H,
J = -17.4, 5.8 Hz), 1.89-1.59 (m, 4H) ppm (the signal for OH
was undetected). 13C NMR (75 MHz, CDCl3): δ = 156.9, 153.9,
148.3, 138.9, 137.1, 137.0, 133.1, 131.8, 131.6, 128.9 (3), 128.5,
127.7, 126.9, 126.7, 125.9, 125.6, 120.8, 64.4, 29.8, 26.2, 22.9,
22.4 ppm. MS (70 eV) m/z: 365 (53) [Mþ], 355 (28), 346 (100), 334
(25), 281 (21), 221 (30), 147 (22), 73 (25). HRMS (ESI) for
C26H24NO: calcd 366.1852, found 366.1856.
127.4, 127.0, 124.9, 123.9, 122.0, 113.6, 113.5, 61.0, 59.3, 56.8,
42.4 ppm. MS (EI, 70 eV) m/z: 366 (74) [Mþ], 365 (100), 351 (25),
349 (24). HRMS (ESI) for C25H23N2O: calcd 367.1805, found
367.1805. Anal. Calcd for 2C25H22N2O(366.45) 3CH3OH(32.04):
3
C, 76.78; H, 6.81; N, 6.76. Found: C, 76.63; H, 6.43; N, 6.72.
1-(2-Methoxy-1-naphthyl)-6-phenyl-7,8-dihydrofuro[3,4-c]-
pyridine (46). When diyne 41 (95 mg, 0.38 mmol) and benzo-
nitrile (3, 74 μL, 0.76 mmol) were reacted according to the
general procedure using CpCo(COD) (4.4 mg, 0.019 mmol,
5 mol %) as the catalyst, compound 46 was isolated after
column chromatography with 79 mg (59%) yield. Mp: 172-
173 °C (THF/n-hexane). HPLC conditions: the compound
turned out to be inseparable under the conditions described
above.30 1H NMR (400 MHz, CDCl3): δ = 8.06-8.03 (m,
2H), 7.95 (d, 1H, J = 9.0 Hz), 7.87-7.83 (m, 1H), 7.69 (s, 1H),
7.53-7.50 (m, 1H), 7.48-7.42 (m, 2H), 7.42-7.36 (m, 3H),
7.37 (d, 1H, J = 9.0 Hz), 5.32-5.24 (m, 2H), 5.05 (dd, 1H, J =
-12.7, 2.0 Hz), 4.77 (dd, 1H, J = -12.7, 1.7 Hz), 3.90 (s, 3H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 156.8, 154.3, 150.6,
149.4, 139.4, 135.4, 133.0, 130.9, 129.3, 129.0, 128.8, 128.2,
127.5, 127.1, 124.7, 123.9, 121.6, 113.4, 112.3, 73.7, 72.6,
56.6 ppm. MS (EI, 70 eV) m/z: 353 (50) [Mþ], 338 (47),
324 (100), 309 (44), 294 (25). Anal. Calcd for C24H19NO2
(353.41): C, 81.56; H, 5.42; N, 3.96. Found: C, 81.54; H, 5.64;
N, 3.88.
2-(2-Methoxy-1-naphthyl)-6-phenyl-7,8-dihydro-5H-cyclopenta-
[c]pyridine (44). Following the general procedure, biaryl 44 was
obtained from 39 (497 mg, 2 mmol) and benzonitrile (3, 412 μL,
4 mmol) as a solid with a yield of 506 mg (72%). Mp: 157-158 °C
(ethyl acetate). HPLC conditions: Chiralpak AD-H, n-hexane/
€
ethanol 90:10, 1.0 mL/min; T1 = 5.5 min, T2 = 6.54 min fur 0 °C.
1H NMR (400 MHz, CDCl3):δ=8.05-8.01 (m, 2H), 7.94 (d, 1H,
J = 9.0 Hz), 7.86-7.83 (m, 1H), 7.70 (s, 1H), 7.46-7.41 (m, 3H),
7.39 (d, 1H, J = 9.0 Hz), 7.40-7.33 (m, 3H), 3.90 (s, 3H), 3.15-
3.09 (m, 2H), 2.84-2.75 (m, 1H), 2.55 (ddd, 1H, J = -16.4, 8.7,
5.6 Hz), 2.18-2.01 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 155.3, 154.4, 151.4, 140.2, 139.7, 133.1, 130.3, 129.3, 128.6 (2),
128.1, 127.5, 126.7, 124.9, 123.7, 122.4, 116.4, 113.7, 56.8, 33.4,
30.7, 24.7 ppm (one carbon signal can not be assigned). MS (EI,
70 eV) m/z: 351 (87) [Mþ], 350 (100), 334 (42), 320 (21). Anal.
Calcd for C25H21NO (351.44): C, 85.44; H, 6.02; N, 3.99. Found:
C, 85.44; H, 6.01; N, 3.52.
Acknowledgment. We thank Prof. Uwe Rosenthal for his
generous support and helpful discussions and dedicate this
work with pleasure to him on the occasion of his 60th
birthday. Financial support from the LIKAT is appreciated.
The excellent technical support from Fabian Fischer and the
analytical department (HPLC: Susanne Schareina and Anja
Kammer; NMR: Dipl.-Ing. Andreas Koch and Dr. Dirk
Michalik) is gratefully acknowledged.
2-(2-Methoxy-1-naphthyl)-N-methyl-6-phenyl-1,3-dihydro-1H-
pyrrolo[3,4-c]pyridine (45). Following the general procedure,
biaryl45 was obtained from40 (527 mg, 2 mmol) andbenzonitrile
(3, 412 μl, 4 mmol) with a yield of 469 mg (64%) as a beige solid.
Mp: 149-150 °C (MeOH). HPLC conditions: see the conditions
described for 44.30 1H NMR (500 MHz, CDCl3): δ = 8.02-7.99
(m, 2H), 7.94 (d, 1H, J = 9.1 Hz), 7.85-7.82 (m, 1H), 7.66 (s,
1H), 7.51-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.39-7.34 (m, 4H),
4.26 (d, 1H, J = -14.4 Hz), 4.22 (d, 1H, J = -14.4 Hz), 3.99 (d,
1H, J = -13.7 Hz), 3.88 (s, 3H), 3.74 (d, 1H, J = -13.7 Hz), 2.63
(s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ = 156.9, 154.3,
150.5, 149.5, 139.7, 134.9, 133.1, 130.7, 129.4, 128.9, 128.8, 128.1,
Supporting Information Available: Synthesis of cobalt
complex CpCo(bpy) as well as the procedures for the reactions
described in Schemes 2 and 3, copies of the proton and carbon
NMR spectra for all compounds, dynamic HPLC spectra for 45
and 46, and crystallographic data for CpCo(bpy) (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 12, 2010 4003